On the heels of a strong Zolgensma sales beat, Novartis' effort to expand the gene therapy's reach has suffered a setback. And a safety red flag is to blame.
The FDA slapped a partial hold on a phase 1/2 trial testing Zolgensma's new spinal-injection formula after worrisome data emerged from a small animal study, Novartis said Wednesday.
The order halts enrollment of patients in the high-dose group of a phase 1/2 trial, which is testing Zolgensma by direct spinal injection. The low- and mid-dose cohorts had already completed enrollment and produced interim results. The spinal muscular atrophy (SMA) treatment is now only approved as an intravenous infusion.
According to Novartis, its gene therapy unit AveXis alerted regulators about dorsal root ganglia mononuclear cell inflammation, sometimes accompanied by neuronal cell body degeneration or loss, that cropped up in a preclinical study. It's a new finding in Zolgensma animal testing.
The condition can be associated with sensory changes, the Swiss drugmaker said, adding that it has not cropped up in humans so far.
In a Wednesday note to clients, SVB Leerink analyst Mani Foroohar suspected the clinical halt is “likely reflective of FDA taking a more stringent attitude towards [Zolgensma] review” after a recent data scandal.
The company said it’s working with the FDA to “identify any additional actions necessary to resume dosing” in the spinal-injection trial, dubbed Strong, and will continue to monitor safety events in patients.
Known as intrathecal delivery, the direct injection into the spine is one avenue Novartis is pursuing to expand Zolgensma’s patient base. The gene therapy is currently only approved for SMA patients younger than two, but the Strong trial is testing it in older SMA type 2 patients up to five years of age.
RELATED: Novartis' latest Zolgensma data bode well for use in older patients
During a conference call last week, Narasimhan said the drug’s future success depends on its ability to tap new markets, including older patients treated via spinal injection. By Foroohar’s estimate, about 39% of Zolgensma’s expected $2.7 billion peak sales would come from patients with later-onset SMA treated with the injectable formula.
AveXis just unveiled positive interim data from the trial's two lower-dose cohorts earlier this month. That data showed patients between two and five years old saw a median increase of 5.9 points from baseline on a common assessment of physical abilities and motor function—almost double the clinically meaningful threshold.
This is not the first time Novartis has scrambled in the face of a Zolgensma safety scare. In April, on the cusp of the drug’s scheduled FDA decision, Novartis said an infant had died in an EU phase 3 trial and that the death was “possibly related to treatment by the investigator.” After an autopsy, the trial researchers concluded in September that the death was not related to Zolgensma.
RELATED: Zolgensma trial death unrelated to gene therapy, Novartis says, touting new data
The clinical halt also follows a Zolgensma data manipulation scandal that angered the FDA. In August, the agency said some animal testing data used in Zolgensma’s application package were falsified. To make it worse, AveXis had known about the problem but didn’t inform the agency until after the drug was approved in May.
Novartis said it had delayed notifying the FDA because it needed to dig through mountains of data to find more details. Both the FDA and Novartis said they believe the drug should remain on the market, but the bad press prompted CEO Vas Narasimhan to promise to disclose any data problem within five business days when a drug review is involved.
RELATED: Novartis' Zolgensma beats data woe, as Mayzent hits reimbursement hurdles
Probably because the data tampering doesn’t affect the commercial product or clinical trial data, the scandal hasn’t hampered Zolgensma’s sales. The drug put up $160 million in the third quarter, crushing the Street’s expectations by 60%.